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BioMed Central Page 1 of 5 (page number not for citation purposes) Head & Face Medicine Open Access Case report Infraorbital cutaneous angiosarcoma: a diagnostic and therapeutic dilemma Tobias Ettl 1 , Johannes Kleinheinz* 2 , Ravi Mehrotra 3 , Stephan Schwarz 4 , Torsten E Reichert 1 and Oliver Driemel 1 Address: 1 Department of Oral and Maxillofacial Surgery, Regensburg University, Germany, 2 Department of Oral and Maxillofacial Surgery, Muenster University, Germany, 3 Department of Pathology, Moti Lal Nehru Medical College, Allahabad University, India and 4 Department of Pathology, Erlangen University, Germany Email: Tobias Ettl - [email protected]; Johannes Kleinheinz* - [email protected]; Ravi Mehrotra - [email protected]; Stephan Schwarz - [email protected]; Torsten E Reichert - [email protected]; Oliver Driemel - [email protected] * Corresponding author Abstract Background: A cutaneous angiosarcoma is a rare malignant tumour of vascular endothelial cells with aggressive clinical behaviour and poor prognosis. Diagnosis is often delayed due to its variable and often benign clinical appearance. Case presentation: This case presents a 64-year-old man with a six-month-history of a recurrent diffuse and erythematous painless swelling below the left eye. Several resections with intraoperatively negative resection margins followed, but positive margins were repeatedly detected later on permanent sections. Histopathologic examination of the specimen diagnosed a cutaneous angiosarcoma. Neither, finally achieved negative margins on permanent sections, nor a following chemotherapy could prevent the recurrence of the disease after five months and the patient's dead 21 months after the first diagnosis. Conclusion: The case elucidates the current diagnostic and therapeutic dilemma of this entity, which shows an unfavourable clinical course in spite of multimodal therapy. Background A cutaneous angiosarcoma (synonyms: lymphangiosar- coma and haemangiosarcoma) is a rare malignant tumour of vascular endothelial cells. It occurs predominantly in the elderly and is confined to the face and the scalp region in more than 50% of cases [1]. Despite the aggressive behaviour and poor prognosis, the diagnosis is often delayed due to its variable and often benign clinical appearance. This case documents a facial cutaneous angi- osarcoma in an elderly male patient, revealing the diag- nostic and therapeutic dilemma of this entity, which shows an unfavourable clinical course in spite of multi- modal therapy. Case report A 64-year-old man presented with a six month history of a recurrent diffuse and erythematous painless swelling (3 × 2 cm 2 ) below the left eye to the Department of Derma- tology, Regensburg University, Germany. Cervical lym- phadenopathy was clinically not detectable. Routine laboratory results showed no abnormality. Presuming an allergic dermatitis, topical treatment with steroids was ini- Published: 11 August 2008 Head & Face Medicine 2008, 4:18 doi:10.1186/1746-160X-4-18 Received: 10 March 2008 Accepted: 11 August 2008 This article is available from: http://www.head-face-med.com/content/4/1/18 © 2008 Ettl et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Page 1: Head & Face Medicine BioMed Central253A10.1186%252F1746-160X-4-18.pdf · BioMed Central Page 1 of 5 (page number not for citation purposes) Head & Face Medicine Case report Open Access

BioMed CentralHead & Face Medicine

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Open AcceCase reportInfraorbital cutaneous angiosarcoma: a diagnostic and therapeutic dilemmaTobias Ettl1, Johannes Kleinheinz*2, Ravi Mehrotra3, Stephan Schwarz4, Torsten E Reichert1 and Oliver Driemel1

Address: 1Department of Oral and Maxillofacial Surgery, Regensburg University, Germany, 2Department of Oral and Maxillofacial Surgery, Muenster University, Germany, 3Department of Pathology, Moti Lal Nehru Medical College, Allahabad University, India and 4Department of Pathology, Erlangen University, Germany

Email: Tobias Ettl - [email protected]; Johannes Kleinheinz* - [email protected]; Ravi Mehrotra - [email protected]; Stephan Schwarz - [email protected]; Torsten E Reichert - [email protected]; Oliver Driemel - [email protected]

* Corresponding author

AbstractBackground: A cutaneous angiosarcoma is a rare malignant tumour of vascular endothelial cellswith aggressive clinical behaviour and poor prognosis. Diagnosis is often delayed due to its variableand often benign clinical appearance.

Case presentation: This case presents a 64-year-old man with a six-month-history of a recurrentdiffuse and erythematous painless swelling below the left eye. Several resections withintraoperatively negative resection margins followed, but positive margins were repeatedlydetected later on permanent sections. Histopathologic examination of the specimen diagnosed acutaneous angiosarcoma. Neither, finally achieved negative margins on permanent sections, nor afollowing chemotherapy could prevent the recurrence of the disease after five months and thepatient's dead 21 months after the first diagnosis.

Conclusion: The case elucidates the current diagnostic and therapeutic dilemma of this entity,which shows an unfavourable clinical course in spite of multimodal therapy.

BackgroundA cutaneous angiosarcoma (synonyms: lymphangiosar-coma and haemangiosarcoma) is a rare malignant tumourof vascular endothelial cells. It occurs predominantly inthe elderly and is confined to the face and the scalp regionin more than 50% of cases [1]. Despite the aggressivebehaviour and poor prognosis, the diagnosis is oftendelayed due to its variable and often benign clinicalappearance. This case documents a facial cutaneous angi-osarcoma in an elderly male patient, revealing the diag-nostic and therapeutic dilemma of this entity, which

shows an unfavourable clinical course in spite of multi-modal therapy.

Case reportA 64-year-old man presented with a six month history ofa recurrent diffuse and erythematous painless swelling (3× 2 cm2) below the left eye to the Department of Derma-tology, Regensburg University, Germany. Cervical lym-phadenopathy was clinically not detectable. Routinelaboratory results showed no abnormality. Presuming anallergic dermatitis, topical treatment with steroids was ini-

Published: 11 August 2008

Head & Face Medicine 2008, 4:18 doi:10.1186/1746-160X-4-18

Received: 10 March 2008Accepted: 11 August 2008

This article is available from: http://www.head-face-med.com/content/4/1/18

© 2008 Ettl et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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tiated. Because of the persistence of the lesion, an inci-sional biopsy was performed three weeks later (Figure 1).Histopathology of the specimen showed an invasivelygrowing tumour of the dermis, composed of atypical vas-cular endothelia in a disordered manner, forming bizarrevascular lumina. The tumor cells were characterized by anelevated proliferated activity with a proliferation fraction(MIB-1) of 5%–10%. The vascular endothelial prolifera-tion showed a papillary architecture accompanied bysmall lymphocytes. The majority of endothelial cells pre-sented a hyperchromatic nucleus and a swollen cyto-plasm. (Figure 2a, 2b, 2c). Immunohistochemical studiesdemonstrated positivity for CD 31 (Figure 2d) and factorVIII-related antigen. Based on these findings the diagnosisof a cutaneous angiosarcoma was made.

After referral of the patient to the Department of Oral andMaxillofacial Surgery, Regensburg University, Germany,

the tumour was removed by wide local surgical excision(Figure 3) and the defect was temporarily covered by Epi-gard. Despite negative intraoperative frozen section mar-gins, positive margins were repeatedly detected later onpermanent sections. Negative margins on permanent sec-tion were finally reached after three resections andinfraorbital soft tissue was plastically reconstructed with abuccal rotation flap. After surgery, chemotherapy fol-lowed with six cycles of alpha-interferon.

Five months later a periorbital redness and swelling onboth sides (Figure 4) required another incisional biopsy,which was confirmed as recurrent angiosarcoma on his-topathological examination. Imaging staging procedures(MRI and CT head-neck, CT chest, CT abdomen, PET andbone scan) found bone invasion to the nasal root (Figure5). Metastases to the neck lymph nodes as well as distantmetastases were clinically and radiologically excluded.

Neither radiochemotherapy with a cumulative radiationdose of 64.8 Gy and seven cycles Doxorubicin nor anadditional antiangiogenetic therapy with Trofosfamide,Pioglitazone, Rofecoxibe and steroids could prevent therapid tumour progression. The patient died 21 monthsafter the first diagnosis.

DiscussionThere are three main types of cutaneous angiosarcoma:Idiopathic angiosarcoma of the head and neck in elderlypatients, lymphoedema-associated angiosarcoma (Stew-art-Treves-Syndrome) and postirradiation angiosarcoma[2]. Besides an association with persistent chronic lym-phoedema, previous irradiation and pre-existing vascularmalformation, little is known regarding the causative fac-tors of that disease [3]. With respect to pathogenesis,among others, upregulation of the glykopeptide VEGF-D,a vascular endothelial growth factor, seems to be respon-sible for the endothelial cell proliferation [4].

Clinically the appearance of a cutaneous angiosarcoma ofthe skin and scalp can be variable. Early lesions most com-monly present as single or multifocal ill-defined, bruise-like erythematous-purplish areas with indurated borders[5]. In the present case, akin to those previously describedby others [6,7], these haematoma-like lesions can be mis-interpreted as benign inflammatory or allergic hypere-mias. More advanced lesions can present as dark bluish,sometimes keratotic papules or nodules with ulcerationand bleeding, mimicking other malignancies like squa-mous cell carcinoma, basal cell carcinoma, malignantmelanoma, lymphoma as well as metastases [3,5,8].

Microscopically a cutaneous angiosarcoma is typicallycharacterized by numerous, irregular and anastomosingvascular channels. These are lined by pleomorphic, hyper-

Clinical appearance after first incisional biopsy: Discreet skin erythema below the left eyeFigure 1Clinical appearance after first incisional biopsy: Dis-creet skin erythema below the left eye.

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chromatic endothelial cells with variable mitotic activity[9]. Immunhistochemical positivity for the endothelialmarkers CD 31 and factor VIII-related antigen as well asfor the transcription factor Fli-1 may help to establishdiagnosis [10,11]. The differential diagnosis includeshemangioma, especially tufted, cavernous and epithelioidhemangioma on the one hand and acantholytic carci-noma on the other hand. Especially in immunocompro-mised patients Kaposi-sarcoma might be a furtherdifferential diagnosis. In the current case the presence ofmany lymphocytes might be a hint to regard the lesion asof lymphatic vessel origin, i.e. as a lymphangiosarcoma.

Treatment of the cutaneous angiosarcoma is generallybased on radical surgery and postoperative radiation ther-

apy. Surgery is postulated to attain a wide excision of thetumour with histologically negative margins [1,4]. Unfor-tunately achieving negative margins is difficult, as multi-focal and extensive microscopic spread is common in thisdisease. Intraoperative frozen sections are often per-formed to assist in determining section margins. Pawlik etal. [5] demonstrated, however, an overall negative predic-tive value of only 33.3% for that procedure, whichexplains the repeating surgical resections in the casereport. For this reason, temporary reconstruction withhomografts or skin substitutes is recommended until thedefinite histological confirmation of margin status. Sinceup to 78% of the patients still have residual tumour afterwide and multiple surgical resections [5,12], this goal ofachieving histologically negative section margins remains

HistopathologyFigure 2Histopathology. a: Overview image: Epidermis, followed by dermis with hair follicles and sebaceous glands. Tumour with unclear borders in the depth (H&E, 16×). b: In detail: Atypic, swollen endothelial cells with anastomosing, pseudopapillar pat-terns and lymphocytic inflammation (H&E, 200×). c: Immunohistochemistry with proliferation marker MIB-1 indicating prolifer-ation in about 5%–10% of the cells (MIB-1, 200×). d: Positive immunohistochemical reaction to the endothelial marker CD 31 (CD 31, 200×).

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debatable. In many cases the resulting extensive resectiondefects require large secondary plastic reconstruction.

More recently, chemotherapy and gene therapy areincreasingly available. Doxorubicin is reported to beactive in angiosarcoma [13], but did not show response inthe present patient. Paclitaxel is another agent, that seemsto have substantial effects, even in patients, who weretreated previously with chemotherapy or radiation ther-apy [2,14]. In more palliative situations, antiangiogentictherapy with pioglitazone, rofecoxib and metronomic tro-fosfamide has been recommended [15].

ConclusionDespite multimodal therapy options, prognosis of thecutaneous angiosarcoma is still poor, with a 5-year-sur-vival rate between 12% and 33%. About half of thepatients are dying within 15 to 18 months of presentation[1,5,16]. The most important positive prognostic factorsseem to be young age, small tumour size, negative resec-tion margins and radiation therapy [3,5,8].

In summary, the present case of a cutaneous angiosar-coma of the face elucidates the current diagnostic andtherapeutic dilemma of this lesion. Diagnosis is often

delayed, due to its putatively innocous clinical appear-ance. Negative microscopic section margins are hardlyachieved during surgery, resulting in multiple operationswith large postoperative defects. Despite multimodal ther-apy concepts, the prognosis remains poor.

Competing interestsThe authors declare that they have no competing interests.

Authors' contributionsTE drafted the manuscript. JK helped to the critical reviewof the article. RM helped to the critical review of the arti-cle. SS performed the histopathological investigations.TER helped to the critical review of the manuscript. ODperformed the surgical procedure, helped to draft themanuscript, helped to the critical review of the manu-script.

Recurrence 5 months after first surgery: Periorbital ery-thema and swelling on both sides (left more than right)Figure 4Recurrence 5 months after first surgery: Periorbital erythema and swelling on both sides (left more than right).

Clinical finding after first surgery: Intraoperative defect, 4 × 2.5 cm2 in sizeFigure 3Clinical finding after first surgery: Intraoperative defect, 4 × 2.5 cm2 in size.

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Consent sectionWritten informed consent was obtained from the patientfor publication of this case report and accompanyingimages. A copy of the written consent is available forreview by the Editor-In-Chief of this journal.

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MRI (axial): Left infraorbital mass with infiltration to the lat-eral nasal rootFigure 5MRI (axial): Left infraorbital mass with infiltration to the lateral nasal root.

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